Diabetic cataract is a significant and costly worldwide health problem. Intracellular osmotic stress has been implicated in the etiology of diabetic cataract. The definition of the sequence of basic molecular and cellular processes leading to the complications of diabetic cataract have yet to be established. The accumulation of organic osmolytes (sorbitol, myo-inositol, taurine) normally protects the lens against osmotic imbalance by maintaining intracellular osmotic homoeostasis. In the course of maintaining lens homeostasis, the lens epithelial layer preserves itself by utilizing several osmotic compensatory mechanisms, whereas the subjacent fiber cells, likely because of a diminished capacity to osmoregulate, swell and bleb. To obtain a realistic view of the pathophysiological impact of osmotic stress on diabetic cataract formation, a novel transgenic animal model has been developed useful to exploring the pathogenesis and therapy of osmotic cataractogenesis. We have successfully introduced the bovine sodium/myo-inositol cotransporter gene (bSMIT) in several mouse lines and have shown the transgene is functionally expressed in developing lens fibers. Lens fiber swelling and consequent cataractous formation provide a physiological surrogate that simulates the progression of human diabetic cataract. Careful scrutiny of mouse lens regional development and early-onset swelling allows for verification of the hypothesis that the lens fibers are incapable of osmoregulation. The molecular biology and the pathophysiology of the transgenic mouse model exhibiting diabetic cataract will be linked by correlating the level of bSMIT gene expression via in situ hybridization and coupled reverse transcription/polymerase chain reaction with the intralenticular content of free myo-inositol. Lens morphology will be followed by light and electron microscopic evaluation of transgenic and nontransgenic littermates using embryonic lenses up through lenses from six month-old mice. Low transgene-expressing mice, which do not form lens opacities with normal rearing and diet, will be made to do so with a myo-inositol supplemented diet. The determination of the sequence of events in the pathophysiology of diabetic cataract formation will identify sites of intervention and allow for the development of innovative pharmacological agents to prevent or halt the progression of diabetic cataract. One such intervention is to activate chloride channels, which enhances both chloride exit and myo-inositol efflux. This study proposes to test the potential usefulness of enhancing myo-inositol efflux through chloride channels as a means for drug therapy to relieve intrafiber osmotic stress.